The present application relates to a diagnostic kit for pancreatic cancer comprising an antibody specifically binding to a complement factor B protein and an antibody specifically binding to a carbohydrate antigen 19-9 protein, a method for providing information for diagnosing pancreatic cancer using the same and a method for diagnosing pancreatic cancer using the same.
Pancreatic cancer (PC; pancreatic ductal adenocarcinoma) caused 330 000 deaths globally in 2012 (WHO Cancer Report 2014) and is predicted to be one of the top three cancer killers along with lung and liver cancers in 2030 (Rahib, L et al., Cancer Res., 2014, 75, 2913-21). According to the ‘Cancer Statistics 2013 Report’, pancreatic cancer not only progresses rapidly but also readily metastasizes to lymph nodes; therefore, early symptoms are rarely recognized and the 5-year survival rate of patients diagnosed with PC is only 1 to 3% (Siegel, R et al., 2013, Ca. Cancer J. Clin. 63, 11-30) Although the surgical removal of tumors is a treatment option, early diagnosis remains difficult and challenging (Lee et al., 2014, J. Proteome Res., 13, 4878-).
One of the causes for lower 5-year survival rate after diagnosis of pancreatic cancer is mainly due to the lack of early diagnosis method or tool, which makes extremely difficult to treat the cancer patients at early stages of disease. Most of symptoms of pancreatic cancer do not appear until it significantly progresses, and thus once pancreatic cancer has been diagnosed, it has already metastasized, so that the surgery is often impossible. In addition, even if the surgery is possible, 80-90% of patients with surgical operation suffers a relapse and lead to death. In order to treat pancreatic cancer patients who received a curative surgery, radiation and chemotherapy are usually implemented but most cases show a limited effect on the survival time of the patient. Therefore, it is very important to diagnose pancreatic cancer at an early stage.
For diagnosis of pancreatic cancer, currently there are several imaging tests of pancreas, which include CT scan for making detailed cross-sectional images of your body, MRI scans for creating detailed images of parts of body and Ultrasound tests for making images of the pancreas (source: American Cancer Society website).
In addition, there are also the blood-based diagnoses which measure particular overexpressed protein in the pancreatic cancer patients' body fluids, such as blood plasma. Currently the most common tumor marker associated with pancreatic cancer is carbohydrate antigen 19-9 (CA 19-9). However, CA 19-9 is elevated in the blood plasma of those patients with cancers of the digestive systems including the biliary tract besides pancreatic cancer, and also in cases of cholangitis without malignant tumor and biliary obstruction, and thus it has very low specificity and sensitivity). In addition, it cannot be used in the early diagnosis, because the normal blood levels of CA 19-9 marker in early cancer appear in many diseases. For example, CA 19-9 is expressed in benign diseases and many types of gastrointestinal cancer (Rosty, C. et al., 2002; Engelen M J et al., 2000; Wu C S et al., 2012).
Meanwhile, complement factor B (CFB), which is one of the key ingredients in alternative pathways of complement activation, has been emerged as a potential diagnostic serologic marker for pancreatic cancer (Lee M J et al., 2014). Alternative pathways are activated by sugar structures on cell surfaces of pathogens, regardless of formation of the antigen-antibody complex. First, the activation is induced by combining a small amount of C3b present in the blood to surfaces of microorganisms. When the C3b is combined with complement factor B in the blood, it is degraded by complement factor D into C3bBb and Ba, in which the C3bBb is stabilized by properidine to generate C3 convertase of the alternative pathway and to enter the amplification phase that create more C3b. As a result, more C3 convertase is generated, and the resulting C3 convertase and C3b are combined to the cell surfaces of microorganisms to form C3bBb3b complex. The formed C3bBb3b complex represents C5 convertase action of the alternative pathway, and degrades C5 into C5a and C5b and finally forms MAC on bacterial surfaces. As a result, the bacteria die, and the antigen is eliminated. Complement factor B is known as a secreted protein playing an important role in generating C5 by combining C3b protein in the initial phase of this alternative pathway, and contains 5 N-glycosylation sites as glycoprotein.
Complement factor B is known to be secreted in sera of various patients suffering from ovarian cancer (Wu. J., et al., JPR, 4541-52, 2012), epipharynx cancer (Seriramalu. R., et al., Electrophoresis, 2388-95, 2010), breast cancer (Doustjalali, S R, et al., Electrophoresis, such as, 2392-401, 2004). Recently, it was shown that IL-6, produced by Pancreatic Stellate Cells—Conditioned Medium highly induced upregulation of CFB, suggesting its association with the progression of pancreatic cancer (Hamada, S. et al., 2016).
However, there was no attempt to diagnose pancreatic cancer with a combination of complement factor B and CA 19-9.